Emily M. Briceño

Frontal and Limbic Activation During Inhibitory Control Predicts Treatment Response in Major Depressive Disorder

BACKGROUND Inhibitory control or regulatory difficulties have been explored in major depressive disorder (MDD) but typically in the context of affectively salient information. Inhibitory control is addressed specifically by using a task devoid of affectively-laden stimuli, to disentangle the effects of altered affect and altered inhibitory processes in MDD. METHODS Twenty MDD and 22 control volunteer participants matched by age and gender completed a contextual inhibitory control task, the Parametric Go/No-go (PGNG) task during functional magnetic resonance imaging. The PGNG includes three levels of difficulty, a typical continuous performance task and two progressively more difficult versions including Go/No-go hit and rejection trials. After this test, 15 of 20 MDD patients completed a full 10-week treatment with s-citalopram. RESULTS There was a significant interaction among response time (control subjects better), hits (control subjects better), and rejections (patients better). The MDD participants had greater activation compared with the control group in frontal and anterior temporal areas during correct rejections (inhibition). Activation during successful inhibitory events in bilateral inferior frontal and left amygdala, insula, and nucleus accumbens and during unsuccessful inhibition (commission errors) in rostral anterior cingulate predicted post-treatment improvement in depression symptoms. CONCLUSIONS The imaging findings suggest that in MDD subjects, greater neural activation in frontal, limbic, and temporal regions during correct rejection of lures is necessary to achieve behavioral performance equivalent to control subjects. Greater activation in similar regions was further predictive of better treatment response in MDD.

Reduced Emotion Processing Efficiency in Healthy Males Relative to Females

This study examined sex differences in categorization of facial emotions and activation of brain regions supportive of those classifications. In Experiment 1, performance on the Facial Emotion Perception Test (FEPT) was examined among 75 healthy females and 63 healthy males. Females were more accurate in the categorization of fearful expressions relative to males. In Experiment 2, 3T functional magnetic resonance imaging data were acquired for a separate sample of 21 healthy females and 17 healthy males while performing the FEPT. Activation to neutral facial expressions was subtracted from activation to sad, angry, fearful and happy facial expressions. Although females and males demonstrated activation in some overlapping regions for all emotions, many regions were exclusive to females or males. For anger, sad and happy, males displayed a larger extent of activation than did females, and greater height of activation was detected in diffuse cortical and subcortical regions. For fear, males displayed greater activation than females only in right postcentral gyri. With one exception in females, performance was not associated with activation. Results suggest that females and males process emotions using different neural pathways, and these differences cannot be explained by performance variations.

Age differences in virtual environment and real world path integration

Accurate path integration (PI) requires the integration of visual, proprioceptive, and vestibular self-motion cues and age effects associated with alterations in processing information from these systems may contribute to declines in PI abilities. The present study investigated age-related differences in PI in conditions that varied as a function of available sources of sensory information. Twenty-two healthy, young (23.8 ± 3.0 years) and 16 older (70.1 ± 6.4 years) adults participated in distance reproduction and triangle completion tasks (TCTs) performed in a virtual environment (VE) and two “real world” conditions: guided walking and wheelchair propulsion. For walking and wheelchair propulsion conditions, participants wore a blindfold and wore noise-blocking headphones and were guided through the workspace by the experimenter. For the VE condition, participants viewed self-motion information on a computer monitor and used a joystick to navigate through the environment. For TCTs, older compared to younger individuals showed greater errors in rotation estimations performed in the wheelchair condition, and for rotation and distance estimations in the VE condition. Distance reproduction tasks (DRTs), in contrast, did not show any age effects. These findings demonstrate that age differences in PI vary as a function of the available sources of information and by the complexity of outbound pathway.

Age and Gender Modulate the Neural Circuitry Supporting Facial Emotion Processing in Adults with Major Depressive Disorder

OBJECTIVES Emotion processing, supported by frontolimbic circuitry known to be sensitive to the effects of aging, is a relatively understudied cognitive-emotional domain in geriatric depression. Some evidence suggests that the neurophysiological disruption observed in emotion processing among adults with major depressive disorder (MDD) may be modulated by both gender and age. Therefore, the present study investigated the effects of gender and age on the neural circuitry supporting emotion processing in MDD. DESIGN Cross-sectional comparison of fMRI signal during performance of an emotion processing task. SETTING Outpatient university setting. PARTICIPANTS One hundred adults recruited by MDD status, gender, and age. MEASUREMENTS Participants underwent fMRI while completing the Facial Emotion Perception Test. They viewed photographs of faces and categorized the emotion perceived. Contrast for fMRI was of face perception minus animal identification blocks. RESULTS Effects of depression were observed in precuneus and effects of age in a number of frontolimbic regions. Three-way interactions were present between MDD status, gender, and age in regions pertinent to emotion processing, including frontal, limbic, and basal ganglia. Young women with MDD and older men with MDD exhibited hyperactivation in these regions compared with their respective same-gender healthy comparison (HC) counterparts. In contrast, older women and younger men with MDD exhibited hypoactivation compared to their respective same-gender HC counterparts. CONCLUSIONS This the first study to report gender- and age-specific differences in emotion processing circuitry in MDD. Gender-differential mechanisms may underlie cognitive-emotional disruption in older adults with MDD. The present findings have implications for improved probes into the heterogeneity of the MDD syndrome.

Distinct cognitive effects of estrogen and progesterone in menopausal women

The effects of postmenopausal hormone treatment on cognitive outcomes are inconsistent in the literature. Emerging evidence suggests that cognitive effects are influenced by specific hormone formulations, and that progesterone is more likely to be associated with positive outcomes than synthetic progestin. There are very few studies of unopposed progesterone in postmenopausal women, and none that use functional neuroimaging, a sensitive measure of neurobiological function. In this study of 29 recently postmenopausal women, we used functional MRI and neuropsychological measures to separately assess the effects of estrogen or progesterone treatment on visual and verbal cognitive function. Women were randomized to receive 90 days of either estradiol or progesterone counterbalanced with placebo. After each treatment arm, women were given a battery of verbal and visual cognitive function and working memory tests, and underwent functional MRI including verbal processing and visual working memory tasks. We found that both estradiol and progesterone were associated with changes in activation patterns during verbal processing. Compared to placebo, women receiving estradiol treatment had greater activation in the left prefrontal cortex, a region associated with verbal processing and encoding. Progesterone was associated with changes in regional brain activation patterns during a visual memory task, with greater activation in the left prefrontal cortex and right hippocampus compared to placebo. Both treatments were associated with a statistically non-significant increase in number of words remembered following the verbal task performed during the fMRI scanning session, while only progesterone was associated with improved neuropsychological measures of verbal working memory compared to placebo. These results point to potential cognitive benefits of both estrogen and progesterone.

Decreased Fronto-Limbic Activation and Disrupted Semantic-Cued List Learning in Major Depressive Disorder.

OBJECTIVES Individuals with major depressive disorder (MDD) demonstrate poorer learning and memory skills relative to never-depressed comparisons (NDC). Previous studies report decreased volume and disrupted function of frontal lobes and hippocampi in MDD during memory challenge. However, it has been difficult to dissociate contributions of short-term memory and executive functioning to memory difficulties from those that might be attributable to long-term memory deficits. METHODS Adult males (MDD, n=19; NDC, n=22) and females (MDD, n=23; NDC, n=19) performed the Semantic List Learning Task (SLLT) during functional magnetic resonance imaging. The SLLT Encoding condition consists of 15 lists, each containing 14 words. After each list, a Distractor condition occurs, followed by cued Silent Rehearsal instructions. Post-scan recall and recognition were collected. Groups were compared using block (Encoding-Silent Rehearsal) and event-related (Words Recalled) models. RESULTS MDD displayed lower recall relative to NDC. NDC displayed greater activation in several temporal, frontal, and parietal regions, for both Encoding-Silent Rehearsal and the Words Recalled analyses. Groups also differed in activation patterns in regions of the Papez circuit in planned analyses. The majority of activation differences were not related to performance, presence of medications, presence of comorbid anxiety disorder, or decreased gray matter volume in MDD. CONCLUSIONS Adults with MDD exhibit memory difficulties during a task designed to reduce the contribution of individual variability from short-term memory and executive functioning processes, parallel with decreased activation in memory and executive functioning circuits. Ecologically valid long-term memory tasks are imperative for uncovering neural correlates of memory performance deficits in adults with MDD.

Stress Response to the Functional Magnetic Resonance Imaging Environment in Healthy Adults Relates to the Degree of Limbic Reactivity during Emotion Processing

Background: Imaging techniques are increasingly being used to examine the neural correlates of stress and emotion processing; however, relations between the primary stress hormone cortisol, the functional magnetic resonance imaging (fMRI) environment, and individual differences in response to emotional challenges are not yet well studied. The present study investigated whether cortisol activity prior to, and during, an fMRI scan may be related to neural processing of emotional information. Methods: Twenty-six healthy individuals (10 female) completed a facial emotion perception test during 3-tesla fMRI. Results: Prescan cortisol was significantly correlated with enhanced amygdala, hippocampal, and subgenual cingulate reactivity for facial recognition. Cortisol change from pre- to postscanning predicted a greater activation in the precuneus for both fearful and angry faces. A negative relationship between overall face accuracy and activation in limbic regions was observed. Conclusion: Individual differences in response to the fMRI environment might lead to a greater heterogeneity of brain activation in control samples, decreasing the power to detect differences between clinical and comparison groups.

Differential prefrontal and subcortical circuitry engagement during encoding of semantically related words in patients with late-life depression

Verbal memory difficulties are common among individuals with late‐life depression (LLD), though there is limited knowledge about disruptions to underlying cerebral circuitry. The purpose of this study is to examine aberrations to cerebral networks implicated in encoding novel verbal semantic material among older adults with LLD.

The double burden of age and major depressive disorder on the cognitive control network

Poor cognitive control (CC) is common among older individuals with major depressive disorder (OMDD). At the same time, studies of CC in OMDD with fMRI are relatively limited and often have small samples. The present study was conducted to further examine poor CC in OMDD with early onset depression, as well as to investigate the interactive effects of MDD and aging on cognitive control. Twenty OMDD, 17 older never-depressed comparisons (ONDC), 16 younger adults with MDD (YMDD), and 18 younger never-depressed comparisons (YNDC) participated. All participants completed the Go level of the Parametric Go/No-Go Test, which requires sustained attention and inhibitory control while undergoing functional MRI (fMRI). YNDC were faster in reaction times (RTs) to go targets relative to the other 3 groups, and the YMDD group was faster than the OMDD group. fMRI effects of both age and diagnosis were present, with greater activation in MDD, and in aging. Additionally, the interaction of age and MDD was also significant, such that OMDD exhibited greater recruitment of fronto-subcortical regions relative to older comparisons. These results are consistent with prior research reporting that OMDD recruit more fronto-striatal regions in order to perform at the same level as their never-depressed peers, here on a task of sustained attention and inhibitory control. There may be an interaction of cognitive aging and depression to create a double burden on the CC network in OMDD, including possible fronto-striatal compensation during CC that is unique to OMDD, as younger MDD individuals do not show this pattern.

Neuropsychological profile and social cognition in congenital central hypoventilation syndrome (CCHS): Correlation with neuroimaging in a clinical case

ABSTRACT Introduction: Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder due to paired-like homeobox gene (PHOX2B) mutations. CCHS patients suffer from dysregulation of the autonomic nervous system characterized by the absence of or extremely reduced response to hypercapnia and hypoxia, with neuropsychological deficits. The aim of this exploratory study is to describe the longitudinal neuropsychological profile and its correlations with magnetic resonance imaging (MRI) of a child with CCHS with a PHOX2B mutation. Method: A comprehensive neuropsychological evaluation was conducted serially at age 7 years 4 months and 10 years 3 months, including assessment of intellectual functioning (IQ), motor functioning, perception, attention, executive functions, language, memory, social cognition, academic skills, and psychopathology. Reliable change index (RCI) scores were used to assess changes between assessments. We collected spin lattice relaxation time (T1)-weighted, fluid-attenuated inversion recovery (FLAIR), and spin spin lattice relaxation time (T2)-weighted images from the child at age 10 years 3 months using a 1.5-tesla MRI scanner. Results: IQ, processing speed index (PSI), social cognition (theory of mind and facial emotion recognition), selective attention, naming, academic skills (reading/comprehension), and manual speed with right hand declined in the second evaluation relative to the initial evaluation, while visuoconstructional praxis, receptive vocabulary, working memory, and arithmetic skill improved. The patient showed a remarkable global deterioration in executive functions (planning, task flexibility, behavioral regulation, and metacognition) as revealed by parental report and clinical evaluation. MRI revealed gliosis from the head to tail of the hippocampus and thinning of parahippocampal gyri. Conclusions: In a clinical case of CCHS, serial evaluation revealed deterioration of executive functions and social cognition over a 3-year interval. These changes corresponded to hippocampal damage as revealed in MRI, which may have affected social cognition through its role in the default mode network. Serial neuropsychological assessment is clinically useful in managing the needs of these patients.